Causal effects of modifiable risk factors on obstructive sleep apnea: A Mendelian randomization study and validation study

Obstructive sleep apnea (OSA) is a chronic condition characterized by recurrent upper airway obstruction during sleep. The pathogenesis of OSA remains unclear, and few studies have systematically investigated causal associations with modifiable risk factors at the genetic level. This study used Mendelian randomization (MR) based on genome-wide association study (GWAS) data to evaluate potential causal effects of 15 modifiable risk factors on OSA. This study used 2-sample MR to assess the causal effects of 15 modifiable risk factors on OSA. Single nucleotide polymorphisms (SNPs) significantly associated with OSA were extracted as instrumental variables from the FinnGen R9 database of pooled GWAS data ( P < 5 × 10 −8 , r 2 < 0.001). SNPs associated with modifiable risk factors were obtained from other GWAS datasets. After harmonizing the exposure and outcome GWAS data, the inverse variance weighting (IVW), weighted median (WM), MR-Egger, weighted model, and simple model were applied to estimate the causal relationship between each risk factor and OSA. The MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) method was used to address heterogeneity and pleiotropic effects. Selected findings were further validated using cross-sectional survey data from the National Health and Nutrition Examination Survey (NHANES) 2005 to 2008. Higher body mass index BMI; OR (odds ratio) = 2.072, 95% confidence interval (CI) = 1.885–2.279, P = 3.94 × 10 −51 , percentage body fat (OR = 1.863, 95% CI = 1.626–2.135, P = 3.37 × 10 −19 ), longer sleep duration (OR = 1.978, 95% CI = 1.385–2.823, P = .013), and hypertension (OR = 2.639, 95% CI = 1.208–5.764, P = .042) were causally associated with increased OSA risk. In contrast, higher educational attainment was associated with a reduced risk (OR = 0.760, 95% CI = 0.665–0.868, P = 5.44 × 10 −5 ). NHANES validation confirmed the associations of BMI (OR = 1.11, 95% CI = 1.09–1.12), body fat percentage (OR = 1.05, 95% CI = 1.03–1.08), and hypertension (OR = 3.31, 95% CI = 2.60–4.22) with OSA. Elevated BMI, body fat percentage, and hypertension are causal risk factors for OSA, whereas higher educational attainment may be protective. These findings suggest preventive strategies targeting modifiable traits could be effective in reducing OSA risk. Further investigation is warranted to clarify the mechanistic pathways linking these exposures to OSA.